New tools enable large-scale studies of gene function

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A molecular library created by a research team led by scientists at the Broad Institute of MIT and Harvard promises to accelerate scientists' understanding of the genetics behind cancer and many biological processes.

In the March 24 issue of Cell, the team, working through the RNAi Consortium (TRC), announced the construction and worldwide availability of a library of molecular reagents that silence most human and mouse genes. The library consists of small RNA molecules, known as RNA-interference (RNAi) inhibitors, that can switch off genes individually. That capability will allow scientists to dissect the genetic underpinnings of normal biology and disease.

TRC is a unique collaboration among academic research institutions and leading life science companies. Its mission is to build comprehensive RNAi libraries and make them available to scientists worldwide. In the coming year, TRC aims to expand the RNAi library to achieve near-complete coverage of the mouse and human genomes. (The library described in Cell is large but not comprehensive.)

"Switching off a single gene through RNAi reveals how that gene functions in a particular biological process. When RNAi's potential is applied to thousands of genes -- as it has been in fruit flies and nematodes -- it can provide a more complete picture of that process," said David Root, director of the RNAi platform at the Broad Institute and director of TRC.

"Thanks to this unique public-private effort, we now have new tools to enable the entire research community to realize the potential of RNAi in the two most important species in biomedicine," said Root, a senior author of the Cell paper.

RNAi gives scientists the ability to turn off an individual gene. Each of the small RNA molecules is tailored to match a fragment of a gene's unique DNA, to which it binds, rendering the gene inactive.

The parallel analysis of thousands of genes using RNAi allows researchers to more readily pinpoint the genes that control a biological process. TRC researchers developed techniques and quality-control measures that make it possible to perform such large-scale analysis.

"The RNAi library developed by the RNAi Consortium is a rich resource for biological discovery," said Nir Hacohen, assistant professor at Massachusetts General Hospital and Harvard Medical School, associate member of the Broad Institute and a senior author. "Ongoing studies in my own laboratory to understand how the immune system senses pathogens and appropriately targets its response will be accelerated using these tools."

To evaluate the RNAi library's performance, the scientists sampled a subset that targets approximately 1,000 human genes. They systematically inactivated these genes in a human cancer cell line to identify the genes that regulate cell division during malignancy. Automated cellular imaging was used to efficiently identify dividing cells in thousands of samples. This approach uncovered more than 100 previously unknown growth regulators, in addition to several known players, confirming the library's sensitivity as a vehicle for gene discovery.

"This critical new tool illustrates the requirement for academic and industry partnerships to drive scientific innovation," said Eric Lander, director of the Broad Institute, a member of the Whitehead Institute for Biomedical Research, an MIT professor of biology, and a senior author on the Cell paper. "The importance of putting these reagents in the public domain will be demonstrated by the many important biomedical discoveries that will stem from them."

Other authors on the paper include David Sabatini, MIT assistant professor of biology, member of the Whitehead and an associate member of the Broad Institute; Bill Hahn, assistant professor at Dana-Farber Cancer Institute and Harvard Medical School, and associate member of the Broad; Sheila Stewart of Washington University, formerly of Whitehead; and Brent Stockwell of Columbia University, also formerly of Whitehead.